Lipid peroxidation studies often employ the use of azo initiators to produce a slow, steady source of free radicals, but the lack of initiators capable of efficiently generating radicals in lipid regions has created persistent problems in these investigations. For example, experiments with symmetrical lipophilic or symmetical hydrophilic azo initiators increasingly suggest that their initiation mechanisms in low-density lipoproteins (LDL) rely upon the presence of alpha-tocopherol to mediate peroxidation. We report here the synthesis and study of the new unsymmetrical azo compounds SA-1, SA-2, C-16, C-12, and C-8 that decompose over a range of convenient temperatures and improve radical generation efficiency and access to lipid compartments. The half-life for decomposition (tau(1/2)) of the unsymmetrical initiators at 37 degrees C in methanol covered a range of 121 hours for SA-1, 77 hours for SA-2, and approximately 25 hours for the series C-16, C-12, and C-8. Agarose gel electrophoresis of LDL incubated with these unsymmetrical initiators supports the conclusion that the initiators associate with lipoprotein without disrupting integrity of the particle. The unsymmetical initiator C-8 when compared to symmetical hydrophilic initiator C-0 is capable of providing increased peroxidation of LDL, as monitored by formation of cholesteryl linoleate oxidation products and consumption of alpha-tocopherol. Efficiency of radical generation in lipophilic and hydrophilic compartments was found to be represented with the use of the radical scavenger combination alpha-tocopherol and uric acid, but not with the use of N,N'-Diphenyl-p-phenylenediamine (DPPD) and uric acid. These unsymmetrical initiators, when compared to the widely used symmetrical azo initiators, provide an advantage of free radical production, lipophilic access, and constant radical generation in the investigation of lipid peroxidation in low-density lipoproteins.